12-0-tetradecanoyl-phorbol-13-acetate (TPA), a potent tumor promoter in vivo, can modulate the proliferative response of mitogen-activated lymphocytes in vitro. TPA itself is nonmitogenic, but it can enhance DNA synthesis by acting as an analogue of interleukin-1, a macrophage lymphokine. In cultures of macrophage-depleted lymphocytes, TPA synergizes with concanavalin A (Con A) wheat germ agglutinin or CA++ ionophores to allow a full proliferative response. In these cases TPA is believed to synergize in interleukin-2 (IL-2) secretion. Recently, it was found that TPA synergizes with IL-2 in the absence of macrophages or lectins to cause proliferation. Therefore TDA behaves as an inducer of IL-2 responsiveness (IL-2 receptors). TPA treatment of cells for some hours prior to stimulation depresses the response to lectins or to allogeneic cells (mixed lymphocyte response). In these cases, a change in T-cell regulation, seems to occur. By marking T cells with sheep red blood cell (SRBC) rosettes, we have identified four subpopulations. TPA, but not the nonpromoting phorbol compounds, can cause a decrease in T cells rosetting with neuraminidasetreated SRBC (EN[unreadable]+[unreadable]) which correlates with an increase in inhibition of lectin stimulation. Moreover, the lectin peanut agglutinin was used to enrich for the suppressor cells. Phenotypically they are PNA[unreadable]+[unreadable] but the TPA induceable precursors are PNA[unreadable]-[unreadable]. (N)